RU2410381C2 - Conversion of 2-pyrazolines to pyrazoles using bromine - Google Patents

Conversion of 2-pyrazolines to pyrazoles using bromine Download PDF

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RU2410381C2
RU2410381C2 RU2007138552/04A RU2007138552A RU2410381C2 RU 2410381 C2 RU2410381 C2 RU 2410381C2 RU 2007138552/04 A RU2007138552/04 A RU 2007138552/04A RU 2007138552 A RU2007138552 A RU 2007138552A RU 2410381 C2 RU2410381 C2 RU 2410381C2
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formula
embodiment
bromine
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compound
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RU2007138552A (en
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Пол Джозеф ФАГАН (US)
Пол Джозеф ФАГАН
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Е.И.Дюпон Де Немур Энд Компани
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between ring members and non-ring members
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

FIELD: chemistry.
SUBSTANCE: invention relates to a method of producing a compound of formula
Figure 00000061
1a, where X denotes a halogen or C1-C4halogenalkyl; Z denotes N or CR9; each R5 independently denotes halogen or C1-C4halogenalkyl; R9 denotes H, halogen or C1-C4halogenalkyl; R10 denotes H or C1-C4alkyl; and n is an integer from 0 to 3, involving bringing 2-pyrazoline of formula
Figure 00000062
2a, where X, Z, R5, R9, R10 and n assume values given above, into contact with bromine in a medium of a suitable inert organic solvent at temperature 80-180°C.
EFFECT: obtaining pyrazoles of formula 1a with high output and purity.
7 cl, 2 tbl, 3 ex

Description

Field of Invention

The invention relates to the conversion of 4,5-dihydro-1H-pyrazoles (also known as 2-pyrazolines) into the corresponding pyrazoles.

State of the art

PCT Patent Publication WO 03/016283 discloses a process for the preparation of pyrazoles of formula i

Figure 00000001

where R 1 represents halogen, R 2 represents, among others, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, CN, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy; R 3 represents C 1 -C 4 alkyl; X represents N or CR 4 ; R 4 represents H or R 2 ; and n is from 0 to 3, provided that when X is CH, then n is at least 1, which are useful as intermediates for insecticides. The method comprises treating the corresponding 2-pyrazoles of formula ii with an oxidizing agent, optionally in the presence of an acid.

Figure 00000002

When X is CR 2 , the preferred oxidizing agent is hydrogen peroxide, and when X is N, the preferred oxidizing agent is potassium persulfate. However, there continues to be a need for new methods that are less costly, more efficient, more flexible or more convenient for work.

SUMMARY OF THE INVENTION

The invention relates to a method for producing a compound of formula 1

Figure 00000003

Where

X represents H, halogen, OR 3 or an optionally substituted carbon group,

L represents an optionally substituted carbon group,

R 1 represents H or an optionally substituted carbon group,

R 2 represents H, an optionally substituted carbon group, NO 2 or SO 2 R 4 ,

R 3 represents H or an optionally substituted carbon group and

R 4 represents an optionally substituted carbon group,

comprising contacting 2-pyrazoline of formula 2

Figure 00000004

with bromine at a temperature of at least about 80 ° C.

The invention also relates to a method for producing a compound of formula 3

Figure 00000005

Where

Z represents N or CR 9 ,

each R 5 independently represents halogen or C 1 -C 4 halogenated,

R 6 represents CH 3 , F, Cl or Br and

R 7 represents F, Cl, Br, I, CN or CF 3 ,

R 8a represents C 1 -C 4 alkyl,

R 8b represents H or CH 3 ,

R 9 represents H, halogen or C 1 -C 4 halogenated, and

n represents an integer from 0 to 3,

using a compound of formula 1a

Figure 00000006

where R 10 represents H or an optionally substituted carbon group, which is characterized by obtaining a compound of formula 1a (i.e., a subspecies of formula 1) by the method described above.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” or any other variation thereof is intended to encompass non-exclusive inclusion. For example, a composition, process, method, object or apparatus that contains a list of elements is not necessarily limited only to these elements, but may include other elements not specifically listed or inherent in such a composition, process, method, object or apparatus. Further, unless expressly indicated otherwise, “or” refers to inclusive or, and not to exclusive or. For example, condition A or B is satisfied by one of the following: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and A and B are true ( or are present).

Also, the indefinite articles “a” and “an” before an element or component of the invention should not be construed as limiting in relation to the number of individual examples (ie, cases) of the element or component. Therefore, “a” or “an” should be understood as including one or at least one, and the verbal form of the singular of an element or component also includes the plural, if it is not obvious that the number should be singular.

As used herein, the term “carbon group” refers to a radical in which a carbon atom is attached to the rest of formulas 1 and 2. When the carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X are substituents , separated from the reactive center, they can cover a wide variety of carbon-based groups obtained by modern methods of synthetic organic chemistry. The process of the invention is generally applicable to a wide range of starting materials of formula 2 and products of formula 1. It is generally preferred that carbon groups are not sensitive to bromine under reaction conditions. However, the present invention is particularly suitable for the conversion of compounds of formula 2 having carbon groups that are sensitive to bromine under other reaction conditions (for example, at temperatures below 80 ° C). A “carbon group” thus includes alkyl, alkenyl and alkynyl, which may be straight or branched chain. A “carbon group” also includes carbocyclic and heterocyclic rings, which may be saturated, partially saturated, or completely unsaturated. Moreover, unsaturated rings can be aromatic if they satisfy the Hückel rule. Carbocyclic and heterocyclic rings of the carbon group can form polycyclic ring systems containing several rings joined together. The term "carbocyclic ring" means a ring in which the atoms forming the main ring are represented only by carbon atoms. The term “heterocyclic ring” means a ring in which at least one of the main atoms of the ring is other than carbon. "Saturated carbocyclic" refers to a ring having a base consisting of carbon atoms bonded to each other by single bonds; Unless otherwise indicated, the remaining carbon valencies are occupied by hydrogen atoms. The term “aromatic ring system” means completely unsaturated carbocycles and heterocycles in which at least one ring in the polycyclic ring system is aromatic. Aromatic indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the plane of the ring, and in which (4n + 2) π electrons, when n is 0 or a positive number, are connected with the ring with compliance with the Hückel rule. The term “aromatic carbocyclic ring system” includes fully aromatic carbocycles and carbocycles in which at least one ring of the polycyclic ring system is aromatic. The term “non-aromatic carbocyclic ring system” means fully saturated carbocycles, as well as partially or fully unsaturated carbocycles in which none of the rings in the ring system is aromatic. The terms “aromatic heterocyclic ring system” and “heteroaromatic ring” include fully aromatic heterocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic. The term "non-aromatic heterocyclic ring system" means fully saturated heterocycles, as well as partially or fully unsaturated heterocycles in which none of the rings in the ring system is aromatic. The term “aryl” means a carbocyclic or heterocyclic ring or ring system in which at least one ring is aromatic, and the aromatic ring provides attachment to the rest of the molecule.

The carbon groups indicated for L, R 1 , R 2 , R 3 , R 4 , R 10 and X are optionally substituted. The term “optionally substituted” in connection with said carbon groups refers to carbon groups that are unsubstituted or have at least one non-hydrogen substituent. Examples of optional substituents include alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, hydroxycarbonyl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, alkylthioalkynylalkenyl, alkenyl, alkylenoyl, alkenyl, alkylenoyl, alkenyl, alkenyl, alkylenyl alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, ari lamino, aminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, arylaminocarbonyloxy, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino and aryloxycarbonylamino, each optionally substituted. Optional additional substituents are independently selected from groups similar to those shown as examples of the substituents themselves to obtain additional groups of substituents for L, R 1 , R 2 , R 3 , R 4 , R 10 and X, such as haloalkyl, haloalkenyl and haloalkoxy. As a further example, alkylamino may be further substituted with alkyl to form dialkylamino. The substituents may also be bonded together, figuratively by the removal of one or two hydrogen atoms from each of the two substituents or substituents, and by a supporting molecular structure and the joining of radicals to form cyclic or polycyclic structures fused or linked to a molecular structure bearing substituents. For example, bonding together adjacent hydroxy and methoxy groups attached, for example, to the phenyl ring, gives a condensed dioxolane structure containing a —O — CH 2 —O— linking group. Binding together the hydroxy group and the molecular structure to which it is attached can give cyclic ethers, including epoxides. Examples of substituents also include oxygen, which when attached to carbon forms a carbonyl functional group. Similarly, sulfur forms a thiocarbonyl functional group upon attachment to carbon. When the 4,5-dihydropyrazole group of formula 2 is a single ring, linking together R 1 and R 2 or L and R 2 will result in a fused bicyclic or polycyclic ring system.

As mentioned herein, “alkyl”, used alone or in compound words, such as “alkylthio” or “haloalkyl”, includes straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl or various butyl isomers pentyl or hexyl. The term “1-2 alkyl” indicates that one or two positions available for the substituent may be occupied by alkyls that are independently selected. "Alkenyl" includes straight or branched alkenes, such as ethenyl, 1-propenyl, 2-propenyl and various isomers of butenyl, pentenyl and hexenyl. Alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and various isomers of butynyl, pentynyl and hexynyl. "Alkynyl" also includes groups containing multiple triple bonds, such as 2,5-hexadiinyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and various butoxy, pentoxy and hexyloxy isomers. "Alkenyloxy" includes straight or branched chain alkenyloxy groups. Examples of “alkenyloxy” include H 2 C = CHCH 2 O, (CH 3 ) 2 C = CHCH 2 O, (CH 3 ) CH = CHCH 2 O, (CH 3 ) CH = C (CH 3 ) CH 2 O and CH 2 = CHCH 2 CH 2 O. "Alkynyloxy" includes straight or branched chain alkynyloxy groups. Examples of "alkynyloxy" include HCCHCH 2 O, CH 3 CHCHCH 2 O and (CH 3 ) CHCHCH 2 CH 2 O. Alkylthio includes straight or branched chain alkylthio groups such as methylthio, ethylthio and various propylthio isomers, butylthio, pentylthio and hexylthio. "Alkylsulfinyl" includes both enantiomers of alkylsulfinyl groups. Examples of “alkylsulfinyl” include CH 3 S (O), CH 3 CH 2 S (O), CH 3 CH 2 CH 2 S (O), (CH 3 ) 2 CHS (O), and various isomers of butyl sulfinyl, pentyl sulfinyl and hexyl sulfinyl. Examples of “alkylsulfonyl” include CH 3 S (O) 2 , CH 3 CH 2 S (O) 2 , CH 3 CH 2 CH 2 S (O) 2 , (CH 3 ) 2 CHS (O) 2, and various butyl sulfonyl isomers, pentylsulfonyl and hexylsulfonyl. Alkylamino, alkenylthio, alkenylsulfinyl, alkenylsulfonyl, alkynylthio, alkynylsulfinyl, alkynylsulfonyl and the like are defined similarly to the above examples. Examples of “alkylcarbonyl” include C (O) CH 3 , C (O) CH 2 CH 2 CH 3 and C (O) CH (CH 3 ) 2 . Examples of “alkoxycarbonyl” include CH 3 OC (= O), CH 3 CH 2 OC (= O), CH 3 CH 2 CH 2 OC (= O), (CH 3 ) 2 CHOC (= O) and various butoxy- isomers or pentoxycarbonyl. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkoxy” includes the same groups bonded through an oxygen atom, such as cyclopentyloxy and cyclohexyloxy. “Cycloalkylamino” means that the nitrogen atom of an amino group is attached to a cycloalkyl radical and a hydrogen atom, and includes groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino. “(Alkyl) (cycloalkyl) amino” means a cycloalkylamino group wherein the hydrogen atom of the amino group is replaced by an alkyl radical, examples include groups such as (methyl) (cyclopropyl) amino, (butyl) (cyclobutyl) amino, (propyl) cyclopentylamino, (methyl) cyclohexylamino etc. “Cycloalkenyl” includes groups such as cyclopentenyl and cyclohexenyl, as well as groups with more than one double bond, such as 1,3- and 1,4-cyclohexadienyl.

The term “halogen” either alone or in complex words such as “haloalkyl” includes fluoro, chloro, bromo or iodo. The term “1-2 halogen” indicates that one or two positions available to the substituent may be occupied by halogen atoms that are independently selected. Furthermore, when used in complex words such as “haloalkyl,” said alkyl may be partially or completely substituted with halogen atoms, which may be the same or different. Examples of “haloalkyl” include F 3 C, ClCH 2 , CF 3 CH 2 and CF 3 CCl 2 .

The total number of carbon atoms in the substituent group is indicated by the prefix "C i -C j ", where i and j mean, for example, numbers from 1 to 3, for example, C 1 -C 3 alkyl denotes methyl to propyl groups.

As indicated above, the carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X may contain an aromatic ring or ring system. Examples of aromatic rings or ring systems include a phenyl ring, 5- or 6-membered heteroaromatic rings, aromatic 8-, 9-, or 10-membered condensed carbobicyclic ring systems, and aromatic 8-, 9-, or 10-membered condensed heterobicyclic ring systems, where each ring or ring system is optionally substituted. The term “optionally substituted” in connection with said carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X refers to carbon groups that are unsubstituted or have at least one non-hydrogen substituent. These carbon groups can be substituted with as many optional substituents as can be provided by replacing the hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Typically, the number of optional substituents (when present) is in the range of one to four. An example of phenyl optionally substituted with one to four substituents is the ring represented by U-1 in Appendix 1, where R v represents a non-hydrogen substituent and r represents an integer from 0 to 4. Examples of aromatic 8-, 9- or 10-membered condensed carbobicyclic ring systems optionally substituted with one to four substituents include a naphthyl group optionally substituted with one to four substituents represented by U-85 and a 1,2,3,4-tetrahydronaphthyl group optionally substituted with one to four by eight substituents, represented as U-86 in Appendix 1, where R v represents a substituent and r represents an integer from 0 to 4. Examples of 5- or 6-membered heteroaromatic rings optionally substituted with one to four substituents include rings from U-2 to U-53, shown in Appendix 1, where R v represents any substituent and r represents an integer from 1 to 4. Examples of aromatic 8-, 9-, or 10-membered fused heterobicyclic ring systems, optionally substituted with one - four substituents include U-54 to U-84 tours are shown in Appendix 1, where R v represents a substituent and r represents an integer from 0 to 4. Other examples of L and R include a benzyl group optionally substituted with one to four substituents, represented by as U-87, and a benzoyl group optionally substituted with one to four substituents, represented as U-88 in Appendix 1, where R v represents a substituent and r represents an integer from 0 to 4.

Although the R v groups are shown in structures from U-1 to U-85, it should be noted that their presence is not necessary, since they are optional substituents. Nitrogen atoms that require substitution to fill their valency are substituted with H or R v . It is noteworthy that some U groups can be substituted with only less than 4 R v groups (for example, U-14, U-15, U-18 to U-21 and U-32 to U-34 can be substituted with only one R v group ) It should be noted that when the connection point between (R v ) r and the U group is illustrated as floating, the (R v ) r group can be attached to any available carbon atom or nitrogen atom of the U group. It should be noted that when the attachment point to group U is illustrated as floating, group U can be attached to the rest of the structure of formula 1 and 2 through any available carbon atom of group U by replacing a hydrogen atom.

Annex 1

Figure 00000007

Figure 00000008

Figure 00000009

Figure 00000010

Figure 00000011

Figure 00000012

Figure 00000013

Figure 00000014

Figure 00000015

Figure 00000016

Figure 00000017

Figure 00000018

Figure 00000019

Figure 00000020

Figure 00000021

Figure 00000022

Figure 00000023

Figure 00000024

Figure 00000025

Figure 00000026

Figure 00000027

Figure 00000028

Figure 00000029

Figure 00000030

Figure 00000031

Figure 00000032

Figure 00000033

Figure 00000034

As indicated above, the carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X may contain saturated or partially saturated carbocyclic and heterocyclic rings, which may be additionally optionally substituted. The term “optionally substituted” in connection with said carbon groups L and R refers to carbon groups that are unsubstituted or have at least one non-hydrogen substituent. These carbon groups can be substituted with as many optional substituents as can be provided by replacing the hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Typically, the number of optional substituents (when present) is in the range of one to four. Examples of saturated or partially saturated carbocyclic rings include optionally substituted C 3 -C 8 cycloalkyl and optionally substituted C 3 -C 8 cycloalkyl. Examples of saturated or partially saturated heterocyclic rings include 5- or 6-membered non-aromatic heterocyclic rings, optionally containing one or two ring members selected from the group consisting of C (= O), S (O) or S (O) 2 , optionally substituted. Examples of such carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X include those shown as structures from G-1 to G-35 in Appendix 2. It should be noted that when the point of attachment to of the indicated G groups is illustrated as floating, the G group can be attached to the rest of the structure of formula 1 or 2 through any available carbon or nitrogen atom of the G group by replacing the hydrogen atom. Optional substituents can be attached to any available carbon or nitrogen atom by replacing a hydrogen atom (these substituents are not shown in Appendix 2, as they are optional substituents). It should be noted that when G contains a ring selected from structures from G-24 to G-31, G-34 and G-35, Q 2 can be selected from O, S, NH or substituted N.

Appendix 2

Figure 00000035

Figure 00000036

Figure 00000037

Figure 00000038

Figure 00000039

Figure 00000040

It is noteworthy that the carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X may be optionally substituted. As noted above, the carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X may usually contain, along with other groups, a U group or a G group, optionally further substituted with one to four substituents. Thus, the carbon groups L, R 1 , R 2 , R 3 , R 4 , R 10 and X may contain a U group or a G group selected from structures from U-1 to U-88 or from G-1 to G-35 and additionally substituted with additional substituents, including from one to four U or G groups (which may be the same or different), wherein the main group of U or G and the substituent groups of U or G may be additionally optionally substituted. Particularly noteworthy are the carbon groups L containing the group U, optionally substituted with one to three additional substituents. For example, L may be a group of U-41.

Embodiments of the present invention include:

Embodiment 1 . A method of obtaining a compound of formula 1, where the molar ratio of bromine to a compound of formula 2 is a ratio of from about 3: 1 to about 1: 1.

Embodiment 2 The method of embodiment 1, wherein the molar ratio of bromine to compound of formula 2 is from about 2: 1 to about 1: 1.

Embodiment 3 . The method of embodiment 2, wherein the molar ratio of bromine to compound of formula 2 is from about 1.5: 1 to about 1: 1.

Embodiment 4 . A process for preparing a compound of formula 1, wherein bromine is added as a gas to a compound of formula 2.

Embodiment 5 . The method of embodiment 4, wherein the bromine gas is diluted with an inert gas.

Embodiment 6 . The method of embodiment 5, wherein the inert gas is nitrogen.

Embodiment 7 The method of embodiment 5, wherein the molar ratio of inert gas to bromine is from about 50: 1 to 2: 1.

Embodiment 8 The method of embodiment 7, wherein the molar ratio of inert gas to bromine is from about 30: 1 to 4: 1.

Embodiment 9 . A method of obtaining a compound of formula 1, where the temperature is above about 100 ° C.

Embodiment 10 The method of embodiment 9, wherein the temperature is above about 120 ° C.

Embodiment 11 A method of obtaining a compound of formula 1, where the temperature is below about 180 ° C.

Embodiment 12 . The method of embodiment 11, wherein the temperature is below about 150 ° C.

Embodiment 13 . The method of embodiment 12, wherein the temperature is below about 140 ° C.

Embodiment 14 . A process for preparing a compound of formula 1, wherein the base is combined with a compound of formula 2 either before or after contacting with bromine.

Embodiment 15 . The method of embodiment 14, wherein the base is selected from tertiary amines (including optionally substituted pyridines) and inorganic bases.

Embodiment 16 . The method of embodiment 15, wherein the base is calcium carbonate and the amount of base is from about 0 to 10.0 equivalents with respect to bromine.

Embodiment 17 . The method of embodiment 16, wherein the amount of base is from about 0 to 4.0 equivalents with respect to bromine.

Embodiment 18 . The method of embodiment 15, wherein the amount of base is from about 0 to 2.4 equivalents with respect to bromine.

Embodiment 19 . A process for preparing a compound of formula 1, wherein the solvent is combined with a compound of formula 2 to form a mixture before being contacted with bromine.

Embodiment 20 . The method of embodiment 19, wherein the solvent is an optionally halogenated hydrocarbon with a boiling point higher than 100 ° C.

Embodiment 21 The method of embodiment 20, wherein the solvent is optionally a chlorinated aromatic hydrocarbon or dibromoalkane.

Embodiment 22 The method of embodiment 21, wherein the solvent is tert-butylbenzene, chlorobenzene or 1,2-dibromoethane.

Embodiment 23 . The method of embodiment 22, wherein the solvent is tert-butylbenzene.

Embodiment 24 . The method of embodiment 22, wherein the solvent is chlorobenzene.

Embodiment 24b . The method according to any one of embodiments 19-24, wherein the temperature is close to the boiling point of the solvent.

Embodiment 25 A process for preparing a compound of formula 1, wherein the molar equivalents of the solvent with respect to the compound of formula 2 are from about 5: 1 to 50: 1.

Embodiment 26 The method of embodiment 25, wherein the molar equivalents of the solvent with respect to the compound of formula 2 are from about 8: 1 to 40: 1.

Embodiment 27 The method of embodiment 26, wherein the molar equivalents of the solvent with respect to the compound of formula 2 are from about 10: 1 to 30: 1.

Embodiment 28 A process for preparing a compound of formula 1, wherein X is halogen, OR 3 or an optionally substituted carbon group.

Embodiment 29 The method of embodiment 28, wherein X is halogen or C 1 -C 4 haloalkyl.

Embodiment 30 The method of embodiment 29, wherein X is Br or CF 3 .

Embodiment 31 The method of embodiment 30, wherein X is Br.

Embodiment 32 . The method of embodiment 28, wherein X is OR 3 .

Embodiment 33 The method of embodiment 32, wherein R 3 is H or C 1 -C 4 haloalkyl.

Embodiment 34 . The method of embodiment 33, wherein R 3 is CF 2 H or CH 2 CF 3 .

Embodiment 35 The method of embodiment 32, wherein R 3 is H.

Embodiment 36 . A process for preparing a compound of formula 1 wherein L is a phenyl ring or a 5- or 6-membered heteroaromatic ring optionally substituted with 1-3 R 5 .

Embodiment 37 The method of embodiment 36, wherein L is pyridinyl or phenyl optionally substituted with 1-3 R 5 , and each R 5 independently is halogen or C 1 -C 4 haloalkyl.

Embodiment 38 . The method of embodiment 37, wherein L is

Figure 00000041

Embodiment 39 The method of embodiment 38, wherein Z is N or CR 9 and R 9 is H, halogen or C 1 -C 4 haloalkyl.

Embodiment 40 The method of embodiment 39, wherein Z is N.

Embodiment 41 The method of embodiment 40, wherein each R 5 independently represents halogen or CF 3 .

Embodiment 42 The method of embodiment 41, wherein the ring is substituted at position 3 with a halogen radical R 5 .

Embodiment 43 The method of embodiment 42, wherein n is 1.

Embodiment 44 The method of embodiment 43, wherein R 5 is Br or Cl.

Embodiment 45 The method of embodiment 39, wherein Z is CR 9 .

Embodiment 46 The method of embodiment 45, wherein R 9 is H, halogen, or CF 3 .

Embodiment 47 The method of embodiment 46, wherein R 9 is halogen.

Embodiment 48 The method of embodiment 47, wherein R 9 is Br or Cl.

Embodiment 49 A method of obtaining a compound of formula 1, where R 1 represents H or C 1 -C 4 alkyl.

Embodiment 50 The method of embodiment 49, wherein R 1 is H.

Embodiment 51 . A process for preparing a compound of formula 1, wherein R 2 is H, CN, C 1 -C 4 alkyl, CO 2 R 10 , NO 2 or SO 2 R 4 , and R 10 is H or C 1 -C 4 alkyl.

Embodiment 52 The method of embodiment 51, wherein R 2 is CO 2 R 10 .

Embodiment 53 The method of embodiment 52, wherein R 10 is H or C 1 -C 4 alkyl.

Embodiment 54 The method of embodiment 53, wherein R 10 is C 1 -C 4 alkyl.

Embodiment 55 The method of embodiment 54, wherein R 10 is methyl or ethyl.

Embodiment 56 . The method of embodiment 51, wherein R 4 is C 1 -C 4 alkyl or optionally substituted phenyl.

Embodiment 57 The method of embodiment 56, wherein R 4 is methyl, phenyl or 4-tolyl.

Additional embodiments include a process for preparing a compound of formula 3 using a compound of formula 1a obtained by the method of any of embodiments 1-57.

The following embodiments are noteworthy.

Embodiment A A method of obtaining a compound of formula 1, where

X represents halogen, OR 3 or C 1 -C 4 halogenated,

L represents a phenyl ring or a 5- or 6-membered heteroaromatic ring, optionally substituted with 1-3 R 5 ,

R 1 represents H,

R 2 represents H, CN, C 1 -C 4 alkyl, CO 2 R 10 , NO 2 or SO 2 R 4 ,

R 3 represents H or C 1 -C 4 halogenated,

R 4 represents C 1 -C 4 alkyl or optionally substituted phenyl,

each R 5 independently represents halogen or C 1 -C 4 halogenated, and

R 10 represents H or C 1 -C 4 alkyl.

Embodiment B The method of embodiment A, wherein the compound of formula 1 is represented by formula 1a

Figure 00000042

and the compound of formula 2 is represented by formula 2a

Figure 00000043

Z represents N or CR 9 ,

R 9 represents H, halogen or C 1 -C 4 halogenated, and

n represents an integer from 0 to 3.

Embodiment C. The method of embodiment B, wherein

X represents Br or CF 3 ,

Z represents N,

each R 5 independently represents halogen or CF 3 , and

R 10 represents methyl or ethyl.

Embodiment D. The method of embodiment B, wherein

X represents OR 3 ,

R 3 represents H or C 1 -C 4 halogenated, and

R 10 represents H or C 1 -C 4 alkyl.

Embodiment E. The method of embodiment D, wherein

X represents OH, OCF 2 H or OCH 2 CF 3 ,

Z represents N,

each R 5 independently represents halogen or CF 3 , and

R 10 represents methyl or ethyl.

Embodiment F. A method of obtaining a compound of formula 1, where the temperature is from about 120 ° C to 140 ° C.

Embodiment G. A process for preparing a compound of formula 1, wherein the base is combined with a compound of formula 2 either before or after contacting with bromine, and molar equivalents of the base with respect to bromine are from about 0: 1 to 4: 1.

Embodiment H. A method of obtaining a compound of formula 1, where the molar equivalents of bromine relative to the compound of formula 2 are from about 2: 1 to 1: 1.

Embodiment I A method of obtaining a compound of formula 1, where the solvent is combined with a compound of formula 2 to form a mixture before contacting with bromine and the temperature is close to the boiling point of the solvent.

Embodiment J. A method for producing a compound of formula 1, wherein bromine is added as a gas to a compound of formula 2 and gaseous bromine is diluted with an inert gas.

Embodiment K The method of obtaining the compounds of formula 3

Figure 00000044

Where

X represents halogen, OR 3 or C 1 -C 4 halogenated,

Z represents N or CR 9 ,

R 3 represents H or C 1 -C 4 halogenated,

each R 5 independently represents halogen or C 1 -C 4 halogenated,

R 6 represents CH 3 , F, Cl or Br, and

R 7 represents F, Cl, Br, I, CN or CF 3 ,

R 8a represents C 1 -C 4 alkyl,

R 8b represents H or CH 3 ,

R 9 represents H, halogen or C 1 -C 4 halogenated, and

n represents an integer from 0 to 3,

using a compound of formula 1a

Figure 00000045

where R 10 represents H or C 1 -C 4 alkyl,

which is characterized by the preparation of a compound of formula 1a by the method of Embodiment B.

Embodiment L. The method of embodiment K, wherein

Z represents N,

each R 5 independently represents Cl, Br or CF 3 ,

one R 5 is in position 3, and

R 10 represents methyl or ethyl.

Embodiment M. The method of embodiment L, wherein X is Br, n is 1, and R 5 is Cl.

As shown in comparative example 1, attempts to oxidize 2-pyrazolines of formula 2 to pyrazoles of formula 1, using bromine as an oxidizing agent, at temperatures close to ambient conditions often lead to adverse reactions involving bromination of the substituent on the pyrazoline or pyrazole ring. It has been found that contacting 2-pyrazoline of formula 2 with bromine at about 80 ° C. or higher can provide the corresponding pyrazole of formula 1 with excellent selectivity, as shown in Scheme 1.

Scheme 1

Figure 00000046

The reaction is carried out by contacting 2-pyrazoline of formula 2, usually in the form of a solution in an inert solvent, with bromine at elevated temperature. The hydrogen bromide by-product is removed either chemically, for example, by adding an appropriate base, or physically, for example, by sparging the reaction mass with an inert gas. After completion of the reaction, the product is isolated by methods known to those skilled in the art, for example, crystallization or distillation.

The process can be carried out in a variety of inert solvents, preferably of low to moderate polarity. Suitable solvents include aliphatic hydrocarbons, halocarbons, aromatic solvents, and mixtures of the above. Aliphatic hydrocarbon solvents include straight or branched chain alkanes such as octane, nonane, decane and the like, as well as mixtures of aliphatic hydrocarbons such as white spirit and naphtha. Carbon solvents include straight or branched chain alkanes substituted with at least one halogen, such as 1,1,2,2-tetrachloroethane, 1,2-dibromoethane and the like. Aromatic solvents include benzene, optionally substituted with one or more substituents selected from halogen, tertiary alkyl and straight or branched chain alkyl, fully substituted with halogen on a carbon atom attached to a benzene ring, and optionally substituted with halogen on other carbon atoms, for example benzene , tert-butylbenzene, chlorobenzene, 1,2-dichlorobenzene, benzotrifluoride, benzotrichloride and the like. The optimum solvent choice depends on the desired process temperature and pressure. If desired, the process can be carried out at higher than ambient pressures in order to increase the boiling point of the solvent. Low pressure can also be used. To facilitate operation, however, the preferred operating pressure is ambient pressure, in which case the boiling point of the solvent should be the same as the desired operating temperature or more. In one embodiment of the invention, the solvent is an optionally halogenated hydrocarbon with a boiling point higher than 100 ° C. Particularly suitable solvents include tert-butylbenzene, chlorobenzene and 1,2-dibromoethane. The molar ratio of solvent to compound of formula 2 is usually from about 50: 1 to 5: 1, preferably from about 40: 1 to 8: 1, and most preferably from about 30: 1 to 10: 1.

According to this invention, the reaction temperature should be raised to a level favorable for oxidation during the completion of bromination in order to maximize the yield of the process. In one embodiment of the method of the invention, the reaction temperatures are usually in the range of about 80 ° C to 180 ° C. In further embodiments, the temperatures range from about 100 ° C. to 150 ° C. and from about 120 ° C. to 140 ° C.

According to the invention, the bromine oxidizing agent may be added either as a liquid or as a gas. In one embodiment, gaseous bromine may be diluted with an inert gas such as nitrogen, helium, argon, and the like. Bromine can be added over such a short period as it allows the removal of hydrogen bromide. In one embodiment, for practical purposes, the bromine addition time is usually from 0.5 to 20 hours, preferably from 0.5 to 10 hours, and most preferably from 1.5 to 4 hours. Although a wide range of reagent ratios is possible, the nominal molar ratio of bromine to compound of formula 2 is usually from about 3 to 1, preferably from about 2 to 1, and most preferably from about 1.5 to 1.

Since hydrogen bromide is formed as a by-product of the reaction of this invention, which in other circumstances could bind to the main centers on the compounds of formulas 1 and 2, or affect the oxidation reaction, the method is usually carried out by removing chemically hydrogen bromide from the solution adding a suitable inorganic or organic base, and / or sparging with an inert gas, and / or heating at reflux temperature. Various inorganic bases may be used, including alkali metal or alkaline earth metal oxides or carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, calcium oxide or the like. Various organic bases may be used, including trisubstituted amines such as triethylamine, N, N-diisopropylethylamine, N, N-diethylaniline or the like, or heteroaromatic bases such as pyridine, picoline, imidazole or the like. In one embodiment of the invention, calcium carbonate is a suitable base for reasons of cost and availability. The base is usually added before bromine is added. As shown in Scheme 1, with the formation of each molar equivalent of pyrazole 1, 2 molar equivalents of a by-product of hydrogen bromide are formed. Therefore, at least 2 molar equivalents of base for each mole of the compound of formula 2 is required to neutralize the by-product of hydrogen bromide. Excess base can be used within the limits of economic feasibility. In one embodiment, the nominal molar equivalent ratio of the loaded inorganic bases to the loaded bromine is from about 2 to 10. In another embodiment, the nominal molar equivalent ratio of the loaded inorganic bases to loaded bromine is from about 2 to 4.

Hydrogen bromide by-product can also be removed from the reaction mass by physical means, for example, by sparging the solution with an inert gas or by heating under reflux. Suitable inert gases include nitrogen, helium, argon and carbon dioxide. An inert gas may be mixed with bromine before being introduced into the reactor. The amount of inert gas must be sufficient to effectively remove hydrogen bromide at the rate at which it is formed. The amount of inert gas required depends on the solvent, the reaction temperature, and the rate of addition of bromine. In one embodiment of the invention, the nominal molar ratio of inert gas to bromine is usually from about 50: 1 to 2: 1, and the inert gas is added during the same period of time that bromine is added. In a further embodiment, the nominal molar ratio of inert gas to bromine is from about 30: 1 to 4: 1. When heated to reflux at the boiling point of the reaction solvent, the vaporized solvent itself can function as an inert gas to remove hydrogen bromide. In one embodiment, the nominal molar ratio of the evaporated solvent to bromine is above about 5 during the addition of bromine. In further embodiments, the ratio is above about 10 and below about 50 of the evaporated solvent to bromine during the addition of bromine.

According to the method of this invention, when hydrogen bromide by-product is removed from the reaction mass by sparging the solution with an inert gas or heating at reflux, the molar ratio of the base present in the reaction mixture to bromine can be less than 2: 1. The nominal molar ratio of the base added to the reaction mixture to bromine is usually from about 0 to 10, preferably from about 0 to 4, and most preferably from about 0 to 2.4.

According to this invention, the solvent is usually combined with the compound of formula 2 to form a mixture and heated at the boiling temperature under reflux before contacting with bromine. When bromine is added to the reaction mixture, the hydrogen by-product of the reaction is removed by simultaneously sparging the reaction mixture with an inert gas and heating at the boiling point under reflux, the reaction temperature is therefore close to the boiling point of the solvent. Therefore, in an embodiment of the invention, the solvent is combined with the compound of formula 2 to form a mixture before contacting with bromine, and the reaction temperature is close to the boiling point of the solvent.

The reaction usually ends within a period of one hour to one day, the progress of the reaction can be monitored by methods known to experts in this field, such as thin layer chromatography and analysis of the spectrum of 1 H-NMR. The resulting pyrazoles of formula 1 can be isolated from the reaction mixture by methods known to those skilled in the art, including extraction, crystallization, and distillation.

As shown in Scheme 2, the compound of formula 1a is a subspecies of the compound of formula 1, wherein X, R 5 , R 10 and Z are as defined above. Compounds of formula 1a can be prepared from the corresponding compounds of formula 2a, which are a subspecies of compounds of formula 2, by the method of this invention as described above.

Scheme 2

Figure 00000047

Compounds of formula 2 can be prepared using a wide variety of modern synthetic methods known to those skilled in the art. Typically, compounds of formula 2, where X represents a carbon group, can be prepared by reacting α, β-unsaturated ketones of formula 4 and hydrazines of formula 5, as shown in broad outline in Scheme 3.

Scheme 3

Figure 00000048

where X represents a carbon group

Compounds of formula 2b can be prepared by contacting compounds of formula 4a with hydrazines of formula 5 (Scheme 4). Compounds of formula 2b may then be alkylated with an alkylating agent Lg-R 3 of formula 6 in the presence of a suitable base to give a compound of formula 2c. The alkylation reaction is usually carried out in a solvent which may contain ethers, such as tetrahydrofuran or dioxane, and in polar aprotic solvents, such as acetonitrile, N, N-dimethylformamide and the like. The base may be selected from inorganic bases such as potassium carbonate, sodium hydroxide or sodium hydride. Preferably, the reaction is carried out using potassium carbonate with N, N-dimethylformamide or acetonitrile as solvent. In the alkylating agent, Lg-R 3 Lg represents a nucleofuge (i.e., a leaving group) such as halogen (e.g. Br, I), OS (O) 2 CH 3 (methanesulfonate), OS (O) 2 CF 3 , OS (O) 2 Ph-p-CH 3 (p-toluenesulfonate) and the like. The product of formula 2c can be isolated by conventional methods, such as extraction.

Scheme 4

Figure 00000049

As shown generally in Scheme 5, compounds of formula 2d, wherein X is halogen, can be prepared by halogenation from the corresponding compounds of formula 2b.

Scheme 5

Figure 00000050

Halogenation reagents that may be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalo trialkyl phosphoranes, dihalogen triphenyl phosphorans, oxalyl chloride and phosgene. Phosphorus oxyhalides and phosphorus pentahalides are preferred. Typical solvents for this halogenation include halogenated alkanes such as dichloromethane, chloroform, chlorobutane and the like, aromatic solvents such as benzene, xylene, chlorobenzene and the like, ethers such as tetrahydrofuran, p-dioxane, diethyl ether and the like. and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and the like. Optionally, an organic base such as triethylamine, pyridine, N, N-dimethylaniline or the like can be added. Addition of a catalyst, such as N, N-dimethylformamide, is also possible.

Alternatively, compounds of formula 2d where X is halogen can be prepared by treating the corresponding compounds of formula 2d where X is another halogen (e.g., Cl to produce a compound of formula 2d where X is Br) with hydrogen bromide or hydrogen chloride, respectively. In this way, the halogen substituent X on the starting compound of formula 2d is replaced with Br or Cl from hydrogen bromide or hydrogen chloride, respectively. The starting compounds of formula 2d, wherein X is Cl or Br, may be prepared from the corresponding compounds of formula 2d, as already described.

For basic links to the preparation of 2-pyrazolines, see Levai A., J. Heterocycl. Chem. 2002 , 39 (1), pp 1-13; El-Rayyes, NR, Al-Awadi NA, Synthesis 1985 , 1028-22 and the references cited therein. Since the compounds of formula 2a are a subspecies of the compounds of formula 2, where X, R 5 , R 10 and Z have the above meanings, the compounds of formula 2a can be obtained by methods already described previously in schemes 3, 4 and 5. Additional links to obtain compounds Formulas 2a, see PCT Publication WO 2003/016283 and WO 2004/011453.

It is understood that certain reagents and reaction conditions described above for the preparation of compounds of formula 2 may not be compatible with the specific functional groups present in the intermediates. In such cases, the inclusion of protection / deprotection or interconversion of functional groups in the synthesis of sequences will contribute to the desired products. The use and selection of protecting groups will be apparent to those skilled in chemical synthesis (see, for example, Greene, TW, Wuts, PGM Protective Groups in Organic Synthesis. 2 nd ed., Wiley: New York, 1991). The specialist should be clear that, in some cases, after the introduction of a given reagent, as indicated in any separate scheme, it may be necessary to carry out additional routine steps of synthesis not specified in detail in order to complete the synthesis of compounds of formula 2. The specialist should also understand that it may be necessary to carry out a combination of the steps explained in the above schemes in a different order than the intended specific sequence presented to obtain the compounds of formula 2. it should also be understood that the compounds of formula 2 and intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidative, and reductive reactions to attach substituents or modify present substituents.

It is assumed that without further development, a person skilled in the art using the preceding description can use this invention in its entirety. The following examples focus on bromination of 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate, as outlined in Scheme 6. Three products may be formed (formulas 8, 9 and 10) when bromine is used as an oxidizing agent for the oxidation of 2-pyrazoline of formula 7. These examples should be construed merely as explanatory and not limiting in any way.

Scheme 6

Figure 00000051

HPLC (HPLC) means high performance liquid chromatography. Spectrum 1 H-NMR is presented in ppm. lower region from tetramethylsilane; “c” means a singlet, “d” means a doublet, “t” means a triplet, “q” means a quartet, “m” means a doublet, “dd” means a doublet of doublets, “dt” means a doublet of triplets, and “shir. s” means wide singlet.

COMPARATIVE EXAMPLE 1

Bromination of 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate at a temperature close to ambient temperature

50.0 g (0.150 mol) ethyl 3-bromo-1- (3-chloro-2-pyridinyl) - are charged into a 2-liter four-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel, reflux condenser and nitrogen inlet 4,5-dihydro-1H-pyrazole-5-carboxyl (for preparation see WO 2003/16283, Example 9), 500 ml of dichloromethane, 200 ml of water and 15.0 g (0.179 mol) of sodium bicarbonate. The biphasic mixture is treated dropwise over a period of about 20 minutes with 25.0 g (0.156 mol) of bromine dissolved in 25 ml of dichloromethane. The temperature of the reaction mass rises from 19 to 25 ° C, and gas is released rapidly during the addition. The resulting orange mixture was kept at ambient conditions for 1 hour. The reaction mass is transferred to a separatory funnel. The dichloromethane layer was separated, dried over magnesium sulfate, filtered and then concentrated on a rotary evaporator. The resulting brown oil (59.9 g) contains, as determined by 1 H-NMR, ethyl 3-bromo-1- (5-bromo-3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5 -carboxylate (91% by weight, formula 8) along with ethyl 3-bromo-1- (5-bromo-3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (2%, formula 9), ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (2%, formula 10) and dichloromethane (5%).

The compound of formula 8:

1 H-NMR (DMSO-d 6 ) δ 8.25 (d, 1H), 8.16 (d, 1H), 5.16 (dd, 1H), 4.11 (q, 2H), 3.61 (dd, 1H, 3.31 (dd, 1H), 1.15 (t, 3H).

The compound of formula 9:

1 H-NMR (DMSO-d 6 ) δ 8.76 (d, 1H), 8.73 (d, 1H), 7.37 (s, 1H), 4.18 (q, 2H), 1.12 (t, 3H).

The compound of formula 10:

1 H-NMR (DMSO-d 6 ) δ 8.59 (d, 1H), 8.39 (d, 1H), 7.72 (dd, 1H), 7.35 (s, 1H), 4.16 (q, 2H), 1.09 (t, 3H).

EXAMPLE 1

Bromination of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate in the presence of pyridine

A: Apparatus for adding gaseous bromine

The experimental apparatus for examples 1A-1C contains a flow meter, a syringe pump, a mixing chamber, a trap, a scrubber and a 10-neck 2-neck flask, in which a water-cooled condenser and a Teflon®-coated thermocouple with wires passing through the capacitor to the measuring tube are inserted to the device. The mixing chamber allows you to mix bromine with nitrogen gas before introducing it into a 2-necked flask, which serves as a reaction vessel. The mixing chamber consists of a 7 ml glass vial closed with a rubber membrane. Nitrogen gas passes through a flowmeter and a Teflon® fluoropolymer tube (1.6 mm O.D.), penetrating the rubber membrane of the mixing chamber. Bromine is injected from the syringe pump into the mixing chamber through a syringe needle piercing the rubber membrane of the mixing chamber. The mixture of bromine and nitrogen exits the mixing chamber through a Teflon® tube piercing the rubber membrane and flows through the tube piercing the rubber membrane on the other neck of the 2-necked flask so that the end of the tube is submerged below the surface of the reaction solution. The reaction flask was heated using an oil bath, and the reaction temperature was monitored with a thermocouple measuring device. A tube connected to the top of the condenser directs the offgase nitrogen gas and non-condensed vapor to a trap and then to a scrubber containing an aqueous solution of sodium bisulfite to capture a by-product of hydrogen bromide and any excess bromine.

EXAMPLE 1A

In the presence of pyridine

0.500 g (1.503 mmol) of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate, 0.256 g (3, 23 mmol) of pyridine and 5.05 g of chlorobenzene and heated to 115 ° C. Bromine (0.265 g, 85 μl, 1.66 mmol) is injected from the syringe into the mixing chamber for 2 hours (i.e. 40 μl / h), while nitrogen is passed through the mixing chamber into the reaction mixture at a speed of 0, 41 ml / s. The flow of nitrogen is maintained for the next half hour. The orange-colored reaction mixture was cooled and then analyzed by quantitative HPLC using O-terphenyl (61.4 mg) as an internal standard. HPLC analytical samples were prepared by adding suspended O-terphenyl to the reaction mixture and 5 ml of dimethyl sulfoxide to dissolve all precipitated salts. An aliquot of 20 μl of the resulting solution was taken and diluted with 1 ml of acetonitrile and filtered through a 0.2 μm frit to obtain an analytical sample for HPLC. The yield is presented in mol.%. HPLC shows that the resulting solution, other than chlorobenzene and pyridine, contains 89% ethyl 3-bromo-1- (5-bromo-3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (formula 10) and 9 % ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (formula 7).

EXAMPLE 1B

In the presence of calcium carbonate

0.500 g (1.507 mmol) ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H- is added to a 10 ml two-necked flask in the apparatus described above, also equipped with a stirrer to facilitate mixing. pyrazole-5-carboxylate, 0.507 g (5.06 mmol) of calcium carbonate and 5.00 g of chlorobenzene and heated to 130 ° C. Bromine (0.265 g, 85 μl, 1.66 mmol) is injected from the syringe into the mixing chamber for 2 hours (40 μl / h), while nitrogen is passed through the mixing chamber into the reaction mixture at a rate of 0.41 ml / s . The flow of nitrogen is maintained for the next 10 minutes. The reaction mixture was cooled and then analyzed by quantitative HPLC using O-terphenyl (51.1 mg) as an internal standard. HPLC shows that the resulting solution, other than chlorobenzene, contains 96% ethyl 3-bromo-1- (5-bromo-3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (formula 10) and 2% ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (formula 7).

EXAMPLE 1C

With nitrogen sparging and no base added

0.25 g (0.76 mmol) of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate and 2, are added to a two-necked flask of the apparatus described above. 5 g of chlorobenzene and heated to 130 ° C. Bromine (0.233 g, 75 μl, 1.46 mmol) is injected from the syringe into the mixing chamber for 3 hours (15 μl / h), while nitrogen is passed continuously through the mixing chamber into the reaction mixture at a speed of 0.46 ml / from. The reaction mixture was cooled and then analyzed by quantitative HPLC using O-terphenyl (32.7 mg) as an internal standard. HPLC shows that the resulting solution, other than chlorobenzene, contains 88% ethyl 3-bromo-1- (5-bromo-3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (formula 10) and 0% ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (formula 7).

EXAMPLE 3

Bromination of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate under various reaction conditions

The following general procedure is used for examples 3-1 to 3-38. Ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate, chlorobenzene and optionally calcium carbonate are charged into a flat-bottomed cylindrical glass vessel (15 mm ID per 80 mm) . The glass vessel is then equipped with a magnetic stirrer, a water-cooled condenser and a Teflon®-coated thermocouple to measure temperature. The reaction mixture is heated to the desired temperature in an oil bath and a stream of nitrogen at a specific flow rate is passed through a Teflon® tube inserted into the reaction mixture. Bromine is added at a controlled rate from a syringe attached to the syringe pump, the syringe is connected via a T-shaped connector to a Teflon® tube through which a nitrogen stream flows, and thus, the bromine is delivered in the vapor phase to the reaction mixture. Exhaust gases are passed through a water trap, which is used to collect hydrogen bromide and any excess bromine that passes through the reaction mixture. After all of the bromine has been added, the reaction mixture is cooled while maintaining the flow of nitrogen. The reaction mixture was prepared for analysis by adding a weighed amount of dimethyl sulfoxide (4.3-4.4 g) containing a known amount of ortho-terphenyl as an internal standard. After thoroughly mixing, an aliquot of 7.5 to 15 μl of this mixture is diluted with 900 μl of acetonitrile, passed through a 0.2 μm filter and analyzed on an Agilent® 1100 Series High Performance Liquid Chromatography instrument. Amount of compound of formula 7, moles of solvent (chlorobenzene) and bromine relative to the starting compound of formula 7, rate of addition of bromine, molar equivalents of base (calcium carbonate) and nitrogen relative to bromine, nitrogen consumption, reaction temperature and reaction results, including% conversion the starting compound of formula 7 and% yields of compounds of formulas 10, 9 and 8 are listed in Table 1 for each example. The reaction yield of each compound of the reaction mixture is indicated as mol% for each example in table 1.

Table 1 Etc. The number of connections. 7 Moth of solvent to the compound. 7 Equ. CaCO 3 to Br 2 Equ. Br 2 Comp. 7 The rate of addition of Br 2 (μl / h) Equ. N 2 to Br 2 Flow rate N 2 (ml / min) Pace. (° C) % Conversion Comp. 7 Mol.% Comp. 10 Mol.% Comp. 9 Mol.% Comp. 8 3-1 1.00 fifteen 0,0 1,0 154 3 4.0 110 52.9 32.8 1,5 18.0 3-2 1.00 fifteen 0.4 1.4 216 2 20,0 110 69.8 33.3 3,1 31.8 3-3 0.67 22 0,0 1,0 103 5 12.0 110 52.6 35.7 1,1 15.1 3-4 0.67 23 1,0 1,2 123 four 20,0 110 62.3 36.8 2,4 21.8 3-5 0.50 thirty 1,2 1,0 77 7 4.0 110 50.8 36.8 0.8 13.5 3-6 0.50 thirty 0,0 1.4 108 5 4.0 110 61.8 37,4 2.1 21.8 3-7 1.00 16 0.9 1.4 86 6 4.0 110 68.8 39.9 4,5 17.7 3-8 1.00 16 1,2 1,0 39 13 20,0 110 59.5 45.9 3.3 8.3 3-9 0.50 thirty 0,0 1,0 19 26 4.0 110 56.7 47.8 1,5 5.5 3-10 0.50 29th 0,0 1,0 31 16 20,0 110 59.5 48.0 2.1 7.1 3-11 1.00 fifteen 0,0 1.4 54 9 20,0 110 73.3 48,2 10.3 11,4 3-12 0.67 22 0.5 1,2 31 16 4.0 110 66.7 49.1 3.2 7.6 3-13 0.50 thirty 0.9 1.4 27 19 20,0 110 80.9 63.5 10.6 5.8 3-14 1.00 16 0,0 1,2 185 3 20,0 120 58.6 38,2 1.9 15.0 3-15 1.00 16 1,0 1,2 185 3 12.0 120 65.9 42.3 2.6 16.3 3-16 0.50 27 0,0 1,0 31 16 4.0 120 65.1 56.9 1,0 3.2 3-17 0.50 thirty 0.4 1.4 108 5 20,0 120 77.7 60.9 4.9 10.1 3-18 0.67 21 0.4 1.4 36 fourteen 4.0 120 89.5 75.3 4.6 1.7 3-19 0.67 22 0.5 1,0 43 12 12.0 120 84.3 77.7 2.6 2,3 3-20 1.00 fifteen 1,2 1,0 39 13 4.0 130 95.9 63.6 0.4 0,0 3-21 0.50 27 0,0 1,0 77 7 4.0 130 70.5 63.6 0.7 0,0 3-22 1.00 16 1,2 1,0 154 3 20,0 130 78.0 67.0 1,2 0,0 3-23 1.00 16 0,0 1.4 216 2 12.0 130 92.3 69.3 8.1 1.4 3-24 0.50 27 0.6 1,0 31 16 12.0 130 88.7 74,2 0.3 2.5 3-25 0.50 thirty 0,0 1,0 77 7 20,0 130 87.0 74.3 0.1 0,0 3-26 1.00 16 0.5 1,2 74 7 4.0 130 93.7 74.7 1,5 0,0 3-27 0.50 27 1,2 1,0 19 26 20,0 130 94.2 78.7 0.3 0,0 3-28 1.00 16 0,0 1,0 39 13 20,0 130 95.6 81.1 0.2 0,0 3-29 0.67 23 0.8 1.4 144 four 4.0 130 92.3 81.2 2.7 1,0 3-30 1.00 fifteen 0,0 1.4 54 9 4.0 130 100.0 83.9 1.4 0,0 3-31 0.50 27 0.9 1.4 27 19 4.0 130 98.6 84.5 0.7 0,0 3-32 1.00 16 0.9 1.4 54 9 20,0 130 99.5 88.5 0.2 0,0 3-33 0.50 27 0.9 1.4 108 5 20,0 130 95.6 89.4 2.2 1,1 3-34 0.67 21 0,0 1.4 58 9 20,0 130 100.0 90.1 0.8 2,3 3-35 0.50 27 0,0 1.4 27 19 20,0 130 99.1 90.3 0.7 0,0 3-36 0.59 25 0.7 1.4 42 12 20,0 130 99,2 92.6 0,0 0,0 3-37 0.60 24 0.8 1,5 43 12 20,0 130 99.3 93.5 0.3 0,0 3-38 0.59 25 0.7 1.4 42 12 20,0 130 100.0 94.9 0,0 0,0

The following abbreviations are used in Table 2: t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl and Bu means butyl. Table 2 illustrates specific conversions for preparing compounds of formula 1a from compounds of formula 2a, according to the method of this invention.

Figure 00000052

Utility

The selective oxidation of 2-pyrazolines with bromine according to this invention can be used to obtain a wide variety of compounds of formula 1, which are useful as intermediates for crop protection agents, pharmaceutical agents and other fine chemicals. Among the compounds obtained according to the method according to this invention, the compounds of formula 1a are particularly applicable for the preparation of compounds of formula 3

Figure 00000053

where X, Z, R 5 and n are as defined above, R 6 is CH 3 , F, Cl or Br, R 7 is F, Cl, Br, I, CN or CF 3 , R 8a is C 1 -C 4 alkyl and R 8b represents H or CH 3 .

Compounds of formula 3 are useful as insecticides as described, for example, in PCT Publication No. WO 01/015518. The preparation of compounds of formulas 2 and 3 is also described in WO 01/015518 and US patent application 60/633899, filed December 7, 2004 [BA9343 US PRV], which are incorporated into this description by reference in their entirety.

Compounds of formula 3 can be prepared from the corresponding compounds of formula 1a by the methods shown in Schemes 7-10.

The carboxylic acid compounds of formula 1a, where R 10 is H, can be prepared by hydrolysis from the corresponding esters of formula 1a, where, for example, R 10 is C 1 -C 4 alkyl. Carboxylic ester compounds can be converted to carboxylic acid compounds in a variety of ways, including nucleophilic cleavage under anhydrous conditions or hydrolytic methods using either acids or bases (for a review of the methods see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis. 2 nd ed., John Wiley & Sons, Inc., New York, 1991, pp 224-269). For compounds of formula 1a, base-catalyzed hydrolytic methods are preferred. Suitable bases include alkali metal hydroxides (such as lithium, sodium or potassium). For example, an ester can be dissolved in a mixture of water and an alcohol, such as ethanol. When treated with sodium hydroxide or potassium hydroxide, the ester is saponified to form the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric or sulfuric acid, gives a carboxylic acid of formula 1a, where R 10 is H. Carboxylic acid can be isolated by methods known to those skilled in the art, including extraction, distillation and crystallization.

As explained in Scheme 7, the coupling of pyrazolecarboxylic acid of formula 1a, where R 10 is H, with anthranilic acid of formula 11 provides benzoxazinone of formula 12. In the method of scheme 7, benzoxazinone of formula 12 is obtained directly by sequentially adding methanesulfonyl chloride to pyrazolecarboxylic acid of formula 1a, where R 10 represents H, in the presence of a tertiary amine such as triethylamine or pyridine, followed by the addition of anthranilic acid of formula 11, then a second addition of a tertiary amine and methanesulfonyl lorida. This procedure usually gives good yields of bezoxazinone of formula 12.

Scheme 7

Figure 00000054

where R 5 , R 6 , R 7 , X, Z and n have the meanings indicated for formula 3.

An alternative method for preparing benzoxazinones of formula 12 is shown in Scheme 8, which involves coupling pyrazolecarboxylic acid chloride of formula 14 with isatoic anhydride of formula 13 to directly produce benzoxazinone of formula 12.

Scheme 8

Figure 00000055

where R 5 , R 6 , R 7 , X, Z and n have the meanings indicated for formula 3.

Solvents such as pyridine or pyridine / acetonitrile are suitable for this reaction. Chlorides of Formula 14 are available from the corresponding acids of Formula 1a, wherein R 10 is H using known techniques such as chlorination with thionyl chloride or oxalyl chloride.

Compounds of formula 3 can be prepared by reacting benzoxazinones of formula 12 with amines NHR 8a R 8b of formula 15, as shown in Scheme 9.

Scheme 9

Figure 00000056

where R 5 , R 6 , R 7 , R 8a , R 8b , X, Z and n have the meanings indicated above for formula 3.

The reaction can be carried out directly between them or in a wide variety of solvents, including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane or chloroform, at optimal temperatures ranging from room temperature to the boiling point of the solvent under reflux. This basic reaction of benzoxazinones with amines to produce anthranilamides is well documented in the chemical literature. For a review of the chemistry of benzoxazinone, see Jakobsen et al., Bioorganic and Medicinal Chemistry 2000 , 8, 2095-2103 and the references cited therein. See also Coppola, J. Heterocyclic Chemistry 1999 , 36, 563-588.

Compounds of formula 3 can also be prepared by the method shown in Scheme 10. Direct coupling of compounds of formula 11 with compounds of formula 1a, wherein R 10 is H, using a suitable coupling reagent such as methanesulfonyl chloride, gives the anthranilamides of formula 3.

Pattern 10

Figure 00000057

Whatever the means of converting a compound of formula 1a to a compound of formula 3, this invention provides an efficient method for preparing a compound of formula 3, which is characterized by preparing a compound of formula 1a by a method for producing a compound of formula 1 as described above.

Claims (7)

1. The method of obtaining the compounds of formula 1A
Figure 00000058

where X is halogen or C 1 -C 4 halogenated;
Z represents N or CR 9 ;
each R 5 independently represents halogen or C 1 -C 4 haloalkyl;
R 9 represents H, halogen or C 1 -C 4 halogenated;
R 10 represents H or C 1 -C 4 alkyl and
n represents an integer from 0 to 3,
including:
contacting 2-pyrazoline of formula 2a
Figure 00000059

where X, Z, R 5 , R 9 , R 10 and n have the above meanings,
with bromine in a suitable inert organic solvent at a temperature of from 80 to 180 ° C.
2. The method according to claim 1, where
X represents Br or CF 3 and Z represents N,
each R 5 independently represents halogen or CF 3 and
R 10 represents methyl or ethyl.
3. The method according to claim 1, where the temperature is between about 120 and 140 ° C.
4. The method according to claim 1, where the base is combined with a compound of formula 2a either before or after contacting with bromine and the molar equivalents of the base with respect to bromine are from about 0: 1 to 4: 1.
5. The method according to claim 1, where the molar equivalents of bromine with respect to the compound of formula 2a are from about 2: 1 to 1: 1.
6. The method according to claim 1, where the solvent is combined with the compound of formula 2a to form a mixture before contacting with bromine and the temperature is close to the boiling point of the solvent.
7. The method according to claim 1, where bromine is added as a gas to the compound of formula 2a and gaseous bromine is diluted with an inert gas.
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